WO 2009/135645 A1 (“WO'645”) discloses a new protecting group for Arg that is derived from indole-3-sulfonyl chloride. It can advantageously be used in peptide synthesis for protecting Arg or other amino acids and has better performance compared to hitherto known protecting groups such as Pbf, this better performance is exemplified in WO'645.
The method for preparation for Arg protected with MIS in the form of H-Arg(MIS)-OH, that is disclosed in WO'645 in examples 1 to 4, has the sequence as given in Formula Scheme 1:

The yield of the steps is given in WO'645 with 96% for Step 1, 78% for Step 2, 18% for Step 3 and 98% for Step 4. Especially Step 3 of WO'645 shows a low yield.
There was a need for a method for preparation of H-Arg(MIS)-OH with a better yield than disclosed in WO'645.
The method of present invention shows higher yield.
The following abbreviations and meanings are used, if not stated otherwise:    Compound of formula (1) 1,2-dimethyl-1H-indol, 1,2-dimethylindol    Compound of formula (2) MIS-OH.Py, Pyridinium 1,2-dimethyl-1H-indole-3-sulfonate    Compound of formula (3) MIS-Cl, 1,2-Dimethyl-1H-indole-3-sulfonyl chloride    Compound of formula (5) L-Arg(MIS)-OH    Compound of formula (6) Fmoc-Arg(MIS)-OH    Compound of formula (PYCAAM) Pyrazole-1-carboxamidine    Compound of formula (SULPYR) sulphur trioxide pyridine complex    DMF Dimethylformamide    DIPEA Diisopropylethylamin    DMAA Dimethylacetamide    DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone    DMSO Dimethyl sulfoxide    EDTA Ethylenediaminetetraacetic acid    Fmoc fluoren-9-ylmethoxycarbonyl    Fmoc-OSu Fmoc N-hydroxysuccinimide ester, compound of formula (Fmoc-OSu)    halogen F, Cl, Br or I, preferably F, Cl or Br, more preferably F or Cl; even more preferably Cl    L-Orn.HCl L-ornithine hydro chloride    MTBE Methyl tert-butyl ether    MIS 1,2-dimethylindol-3-sulfonyl    NMP N-Methyl-2-pyrrolidone    Pbf 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl    WO'645 WO 2009/135645 A1    Z benzyloxycarbonyl